Kojro Elzbieta, Postina Rolf, Buro Corinna, Meiringer Christoph, Gehrig-Burger Katja, Fahrenholz Falk
Institute of Biochemistry, Johannes Gutenberg University, Becherweg, Mainz, Germany.
FASEB J. 2006 Mar;20(3):512-4. doi: 10.1096/fj.05-4812fje. Epub 2006 Jan 9.
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has neurotrophic as well as anti-apoptotic properties and is involved in learning and memory processes. Its specific G protein-coupled receptor PAC1 is expressed in several central nervous system (CNS) regions, including the hippocampal formation. Here we examined the effect of PAC1 receptor activation on alpha-secretase cleavage of the amyloid precursor protein (APP) and the production of secreted APP (APPsalpha). Stimulation of endogenously expressed PAC1 receptors with PACAP in human neuroblastoma cells increased APPsalpha secretion, which was completely inhibited by the PAC1 receptor specific antagonist PACAP-(6-38). In HEK cells stably overexpressing functional PAC1 receptors, PACAP-27 and PACAP-38 strongly stimulated alpha-secretase cleavage of APP. The PACAP-induced APPsalpha production was dose dependent and saturable. This increase of alpha-secretase activity was completely abolished by hydroxamate-based metalloproteinase inhibitors, including a preferential ADAM 10 inhibitor. By using several specific protein kinase inhibitors, we show that the MAP-kinase pathway [including extracellular-regulated kinase (ERK) 1 and ERK2] and phosphatidylinositol 3-kinase mediate the PACAP-induced alpha-secretase activation. Our findings provide evidence for a role of the neuropeptide PACAP in stimulation of the nonamyloidogenic pathway, which might be related to its neuroprotective properties.
神经肽垂体腺苷酸环化酶激活多肽（PACAP）具有神经营养和抗凋亡特性，并参与学习和记忆过程。其特异性G蛋白偶联受体PAC1在包括海马结构在内的几个中枢神经系统（CNS）区域表达。在此，我们研究了PAC1受体激活对淀粉样前体蛋白（APP）的α-分泌酶切割及分泌型APP（APPsα）产生的影响。用人神经母细胞瘤细胞中的PACAP刺激内源性表达的PAC1受体可增加APPsα分泌，而PAC1受体特异性拮抗剂PACAP-(6 - 38)可完全抑制这种分泌。在稳定过表达功能性PAC1受体的HEK细胞中，PACAP - 27和PACAP - 38强烈刺激APP的α-分泌酶切割。PACAP诱导的APPsα产生呈剂量依赖性且具有饱和性。基于异羟肟酸的金属蛋白酶抑制剂，包括一种优先作用于ADAM 10的抑制剂，可完全消除PACAP诱导的α-分泌酶活性增加。通过使用几种特异性蛋白激酶抑制剂，我们发现丝裂原活化蛋白激酶途径[包括细胞外调节激酶（ERK）1和ERK2]和磷脂酰肌醇3激酶介导了PACAP诱导的α-分泌酶激活。我们的研究结果为神经肽PACAP在刺激非淀粉样生成途径中的作用提供了证据，这可能与其神经保护特性有关。
